Summary for 7P1L
| Entry DOI | 10.2210/pdb7p1l/pdb |
| Descriptor | MAP/microtubule affinity-regulating kinase 3, 5-Bromo-4-N-[2-(1H-imidazol-5-yl)ethyl]-2-N-[3-(morpholin-4-ylmethyl)phenyl]pyrimidine-2,4-diamine, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | kinase inhibitor active site folded activation loop uba domain, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 76500.09 |
| Authors | Dederer, V.,Preuss, F.,Chatterjee, D.,Vlassova, A.,Mathea, S.,Axtman, A.,Knapp, S. (deposition date: 2021-07-01, release date: 2021-07-14, Last modification date: 2024-01-31) |
| Primary citation | Drewry, D.H.,Annor-Gyamfi, J.K.,Wells, C.I.,Pickett, J.E.,Dederer, V.,Preuss, F.,Mathea, S.,Axtman, A.D. Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration. J.Med.Chem., 65:1313-1328, 2022 Cited by PubMed Abstract: The pyrimidine core has been utilized extensively to construct kinase inhibitors, including eight FDA-approved drugs. Because the pyrimidine hinge-binding motif is accommodated by many human kinases, kinome-wide selectivity of resultant molecules can be poor. This liability was seen as an advantage since it is well tolerated by many understudied kinases. We hypothesized that nonexemplified aminopyrimidines bearing side chains from well-annotated pyrimidine-based inhibitors with off-target activity on understudied kinases would provide us with useful inhibitors of these lesser studied kinases. Our strategy paired mixing and matching the side chains from the 2- and 4-positions of the parent compounds with modifications at the 5-position of the pyrimidine core, which is situated near the gatekeeper residue of the binding pocket. Utilizing this approach, we imparted improved kinome-wide selectivity to most members of the resultant library. Importantly, we also identified potent biochemical and cell-active lead compounds for understudied kinases like DRAK1, BMP2K, and MARK3/4. PubMed: 34333981DOI: 10.1021/acs.jmedchem.1c00440 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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